title: Functional consequences of two HTR2C polymorphisms associated with antipsychotic-induced weight gain.
abstract: BACKGROUND
  Genetic variation in the promoter region of HTR2C encoding for the 5-HT(2C) receptor is associated with antipsychotic-induced weight gain. Several studies have investigated the regulatory potential of associated variants using gene-reporter systems. Establishing associated polymorphisms as causal variants may aid in the identification of the molecular mechanisms of phenotypic variation.
  
  
  OBJECTIVE
  To this end we examined the binding of nuclear factors from rat hypothalamus to two polymorphisms in HTR2C, rs3813929 (-759C/T) and rs518147 (-697C/G) using electromobility shift assays. For rs518147, allele-specific RNA folding was also investigated.
  
  
  RESULTS
  Both polymorphisms bound nuclear factors, identifying the sequence fragments as regulatory elements. Importantly, rs3813929 (-759C/T) altered DNA-protein interactions with the weight gain-resistant allele abolishing the formation of two complexes. The formation of allele-specific RNA loops was also observed for rs518147.
  
  
  CONCLUSIONS
  These data establish rs3813929 (-759C/T) as a functional polymorphism and suggest disruption of DNA-protein interactions as a mechanism by which HTR2C expression is perturbed leading to an influence on antipsychotic-induced weight gain.
authors.affiliation: Division of Psychiatry & Neuroscience, Queen's University Belfast, Whitla Medical Building, 97 Lisburn Road, Belfast BT97BL, UK. matthew.hill@kcl.ac.uk
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Hill
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Reynolds
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects*; D014644:Genetic Variation / Q000235:genetics; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011485:Protein Binding / Q000235:genetics; D025941:Protein Interaction Mapping / Q000379:methods; D051381:Rats; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics* / Q000502:physiology; D015430:Weight Gain / Q000187:drug effects* / Q000235:genetics*
chemical_list: D014150:Antipsychotic Agents; D044405:Receptor, Serotonin, 5-HT2C